The general aim of this project is to elucidate mechanisms by which proteins and viruses enter cells by receptor-mediated transport processes and translocate across the lipid bilayer to cytosol and nuclear compartments. Molecular signals which lead to unique vesicle trafficking are studied. Basic knowledge from these processes is used to design targeted drug delivery systems such as immunotoxins. Anti-rhesus CD3 Immunotoxins constructed with CRM9, a binding site mutant of diphtheria toxin, deplete peripheral blood T cells to levels below 200 T-cell/mm3 for 48 hours or longer. Anti-rhesus CD3 antibody alone depletes T-Cells for only 24 hours. The conjugate is also effective at depleting lymph node T cells whereas the antibody alone has little effect on this compartment. Systemic toxicity has not yet been reached. The therapeutic margin appears promising for clinical application which might include treatments for AIDS, autoimmune diseases and graft-versus-host- disease following bone marrow transplantation. Pre-clinical trials in non-human primates are continuing.